Malaria and lymphatic filariasis are mosquito-borne diseases that cause morbidity and mortality in hundreds of millions of people throughout the tropics and subtropics of both hemispheres. The emergence of drug resistant parasites and pesticide resistant vector populations is having a major negative impact on traditional methods used in control programs. This program proposal is designed to use contemporary biochemical and molecular tools to develop new approaches for interruption of the parasite life cycle at the level of the mosquito vector. The four projects that comprise this proposal provide a unified and systematic approach towards our ultimate goal of determining at the genetic level those factors that influence vector competence of mosquitoes for malaria parasites and filarial worms and using this information to develop novel control strategies. The basic aims of the proposed research are (1) the identification of candidate genes that impart resistance to the vector, (2) the testing of these candidate clones in vivo to verify their biological effects, (3) the development of selectable markers suitable for the transformation of mosquitoes, and (4) the development of virus expression systems both to cytoplasmically transform mosquito ells in vivo and as a new generation of biocontrol agents. Christensen will identify and characterize genes and their products relative to vector competence in lymphatic filariasis. Christensen will identify and examine candidate genes that control the resistance of Anopheles gambiae for Plasmodium infection. Christensen will develop insecticide resistance genes as selectable markers suitable for the transformation of both cultured mosquito cells lines and mosquitoes themselves, and Beatty will exploit viruses that naturally infect mosquitoes to investigate the molecular biology of vector-pathogen interactions and to develop new biocontrol agents. Each of these projects by themselves would provide a significant contribution to our understanding of vector biology and vector-pathogen associations, but the collaborative nature and synergistic interactions of this program project will provide much greater insight into the genetic basis of vector competence in mosquitoes and consequently should provide the knowledge and tools required to actually formulate new control strategies for mosquito-borne diseases.